Production of 11beta,17alpha-dihydroxy-1-methyl-17beta(1-oxo-2-hydroxyethyl)-4-estren-3-one and 11beta,17alpha-dihydroxy-1-methyl-17beta(1-oxo-2-hydroxyethyl)-4,6-estradiene-3-one and esters thereof



Patented Jan. 22, 1953 United States Patent Q PRODUCTION (BF 115,17oc-D1HYDROXY-1-METH- YL- 176(1-OX0-2-HYDROXYETHYL) 4 ESTREN- 3-0NE AND 115,17d-DIHYDROXY 1 METHYL- 17 5(1 X0 2 HYDROXYETHYL)-4,6-ESTRADI- ENE-Zl-ONE AND ESTERS THEREOF John M. Chemerda and Arthur E. Erickson, Metuchen, N.J., assignors to Merck & Co., Inc., Railway, N.J., a corporation of New Jersey No Drawing. Filed May 16, 1958, Ser. No. 735,706

10 Claims. (Cl. 260-23955 This application is a continuation-in-part of our copending application Serial No. 690,428, filed October 16, 1957, now abandoned.

This invention is concerned generally with novel steroid compounds and with processes of preparing the same. More particularly, it relates to l1,8,l7u-dihydroxylmethyl-17B-(l-oxo- -hydroxyethyl) -4-estren 3 one and l113,17a-dihydroxy-l-methyl 17B (l-oxo-Z-hydroxyethyl)-4,6-estradiene-3-one and esters thereof and to the processes of preparing these compounds. It is also concerned with the novel chemical compounds produced as intermediates in the synthesis.

The chemical compounds with which this invention is concerned, namely, l1B,17a-dihydroxy-l-methyl-l7a-(loxo-Z-hydroxyethyl) -4-estrene-3 one and 113,170: dihydroxy-l-methyl-l7B-(l-oxo-2-hydroxyethyl) 4,6 estradiene-3-one and esters thereof possess anti-inflammatory activity and are efiective in the treatment of arthritis and related diseases.

In preparing our novel chemical compounds, we utilize as a starting material either l7u,2l-diacetoxy-l,4-pregnadiene-3,1l,20-trione or l7u.,'2l-diacetoxy-l,4,6-pregnatriene-3,1l,20-trione which may be represented by the following formulaomoac CH D AC Either of the above compounds can be reacted with acetic anhydride, in the presence of acetic acid and zinc chloride, which is employed as a catalyst, to form 3,l7a-diacetoXy-l-methyl-l7,8-(l-oxo 2 acetoxyethyD- 1,3,5(l0)-estratrien-ll-one or 3,17-diacetoxy 1 methyll75-(l-oxo-Z-acetoxyethyl) l,3,5(10) 6 estratetraenll-one, which may be identified by the formulae- H O ZOAG =0 p om (ilHaOAc C=O Upon hydrolysis of either one of the above compounds with sodium methylate in methanol, the acetyl groups are replaced by hydrogen in the 3, 17a, and 21 positions to yield 3,17 a-dihydroxy-l-methyl-fl B-(l oxo-Z hydroxyethyl)-l,3,5(l0)-estratrien-1l-one or 3,17oc-dihYdl0XY lmethyl-l7B-(l-oxo-Z-hydroxyethyl) 1,3,5 (l0),6 estratetraen-ll-one which have the following structural formulae-- CHzOH i i ill g Reaction of either of the above compounds with diazomethane results in the substitution of a methoxy group for the hydroxy group in the 3-position, to form 1704- hydroxy-3-methoxy-1-methyl-l7[3-(l-oxo 2 hydroxyethyl) -1 ,3 ,5 10) -estratrien-1 l-one or 17 a-hydroXy-B-methoxy-l-methyl-flfi-(l-oxo-Z hydroxyethyl) l,3,5(l0),6-

4 estratetraen-ll-one which may be represented as folor 1WS omon CHzOH 5 I"OH: l OH HO CH 9H3 I I I 10 cmo CHaO- a Treatment of the above compound with formalin results in the formation of llp-hydroxy-3-methoxy-1-methy1-l7,20,20,21 bis (dioxymethylene) 1,3,5 10) estra- CHQOH triene or 11 3 hydroxy-3-methoxy-l-methyl-17,20,20,21- 8: bis-'(dioxymethylene)-1,3,5(10),G-estratetraen which may A, be represented by the following structural formula- CH i l 3 l oH= 0 cmor I 0 HO Treatment of either of the above compounds with semicarbazide yields 17m-hydroxy-3-rnethoxy 1 -methyl- 7 17;8(1-semicarbazono-2-hydroxyethyl) 1,3,5 (10) estra- I trien-ll-one 0r 17a-hydroxy-3-methoxy-l-methyl-17fi-(1- semicarbazono-2-hydroxyethyl) 1,3,5 10),6 estrate- C1130 trae-ll-one which may be represented as follows: I

OHzOH 4 H,0-0 o=NNHooNm on: ..()H 0 v 0113?, l v I OH:

HO OH O- or V I omon OHaO O=NNHOONH2 Either of the above-identified compounds is reduced I OH with lithium and the residue reacted with formic acid to 0: form 11,9,17a-dihydroxy-l-methyl-17,B-(l-oxo-2-hydroxy- OH; ethyl) -4-estren-3-one or 11,8,17a-dihydroxy-l-methyl-17 3- I 1-oXo-2-hydroxyethyl)-4,6-estradien-3-one which may be represented by the following formula- OHSO CHsOH O ---0H Upon reacting either of the above compounds with HO sodium borohydride and acidifying the reduction prod- CH3 ucts, there is formed l1,8,17u-dihydroxy- 3 -methoxy-lmethyl 17,8 (l 0x0 2 hydroxyethyl) 1,3,5(10)- estratriene or 115,170: dihydroxy 3-methoxy-1-methyl- 17 8-(1-oxo-2 hydroxyethyl) 1,3,5(10),6 estratetraen which have the structural formulae onion 232011 00 L---OH L--.0H HO- HO- :1 ([3113 l CH3 CHsO O aovaeaa The 11 B,17c'.-dihydroxy- 1-methyl-17B-(1-oxo-2-hydroxyethyl) -4-estren-3-one or 115,17a-dihydroxy-l-rnethyl-U {3- (l-oxo-Z-hydroxyethyl)-4,6-estradien-3-one obtained as above can be reacted with acylating agents such as lower allcanoic anhydrides, benzoic anhydride and the like to produce other 1 l5,17 z-dihydroxy-1-methyl-17{3-(1-oxo-2- acyloxyethyl)-4-estrene, l1B,17ot-dihydroxy-l-methyl-l7(3- (1-oxo-2-acyloxyethyl)-4,6-estradiene-3-one such as 116, 17st dihydroxy l methyl-17,641-oxo-2-propionoxyethyl) -4-estrene-3-one, 115,17a dihydroxy-l-methyl-Ufi-(loxo-Z-propionoxyethyl) -4,6-estradiene-3-one, 11p, 17 oc-dihydrox l-methyl- 17 ol-oxo-2-butyroxyethyl) -4-estrene- 3 one, l1e,l7a-dihydroxy-l-rnethyl-175-(l-oxo-Z-butyroxyethyl) 4,6 estradiene 3 one, 115,17a-dihydroxy-1- methyl-17 13-( 1-oxo-2-tertiarybutylacetoxyethyl) -4-estrene- 3 one, 1113, l7ot-dihydroxy-l-methyl-Ufi-(l-oxo-Z-tertiarybutylacetoxyethyl) -4,6-estradiene-3-one, 11p,17ct-dihydroxy-1-'nethyl-17B-(1-oxo-2-benzoxyethyl)-4-estrene 3- one, 11,8,l7u dihydroxy-l-methyl-l7B-(l-oxo-2-benzoxyethyl)-4,6-estradiene-3-one, and the like.

In accordance with one embodiment of this invention, it has been found that the rearrangement of l7ct,2l-diacetoxy-l,4-pregnadiene-3,11,20-trione to 3 5,17a-diacetoxyl-methyl-lm-(l oxo 2 acetoxyethyl)-1,3,5(l)-estratrien-ll-one can be achieved without serious damage to the side chain if zinc chloride-acetic acid is used as a catalyst in acetic anhydride solution. At 25 C. conversion to the phenol is complete after four days. This reaction is unusual in that 1,17a-diacetoxy-4-methyl-17,8-(1-oxo-2- acetoxyethyl) 1,3,5(10) estratrien-ll-one would have been expected.

The hydrolysis of 3,17a-diacetoxy-1-methyl 17B (1- oxo 2 hydroxyethyl)-1,3,5(10)-estratrien-11-one is carried out under extremely mild conditions since the side chain decomposes rapidly on exposure to strong alkali.

The following examples are to be understood as illustrative only and are in no way to be construed as limiting the invention.

EMMPLE 1 Preparation of 3,17m-Diacet0xy-1-Methyl-17B (1-Ox0-2- Ace toxycthyl -1 ,3 ,5 (l O)-.Estratrien-1I-One To a solution containing 2 grams of 17u,21-diacetoxy 1,4 pregnadiene 3,11-20 trione prepared as described hereinafter, in 80 cc. of acetic anhydride is added 8 cc. of a solution of anhydrous zinc chloride in glacial acetic acid. After purging with nitrogen, the solution is stored at 25 C. for four days. The reaction mixture is quenched in 1500- cc. ice water and stirred until the acetic anhydride has hydrolyzed. The 3,l7ot-diacetoxy-l-methyl-l7B-(l-oxo-2-acetoxyethyl) -1,3,5 (10) -estratrien-l l-one is isolated by extraction with ether-benzene. The extract is washed successively with ice water, cold 5% sodium bicarbonate solution, ice water and then dried over anhydrous sodium sulfate. The solution is evaporated to dryness in vacuo and 2.2 grams of 3,17u-diacetoxy-1-methy1- 17 Q-( 1-oxo-2-acetoxyethyl) -1,3,5 10) -estratrien-1 1-one is recovered.

T he 17a,21-diacetoxy-1,4-pregnadiene 3,11,20 trione used as a starting material in Example 1 is prepared starting with the known 17,2l-diacetoxy-4-bromopregnane-3, 11,20-trione in accordance with the following procedure:

To a suspension of 5.04 g. of 1711.,21-diacetoxy-4-brornopregnane-3,ll,20-trione in 90 ml. of acetic acid containing 1 ml. of a 0.95 N solution of hydrogen bromide in glacial acetic acid is added a solution of 1.55 g. of bromine in glacial acetic acid (10 ml). The mixture is stirred as the bromine is added over twenty-two minute period, and the temperature remains at 2511 C. The

bromine is rapidly consumed as evidenced by decolorization. To the mixture is then added 0.9 g. of anhydrous sodium acetate, and then, slowly, 500 ml. of water which causes the separation of a granular product. This crude 17a,2l-diacetoxy-2,4-dibrornopregnane 3,11,20 trione is collected on a filter and air-dried. The crude material melts at 132-138 C. with decomposition. I

A mixture of 5 ml. of 2,4,6-collidine and 5 ml. of dimethylformamide is heated to 135 C., and a solution of 1.5 g. of 17et,21-diacetoxy-2,4-dibromopregnane-3,11,20- trione in 5 ml. of dimethylformamide is added. The resulting mixture is heated to reflux, and is refluxed for two hours. The mixture is then cooled in ice, causing the separation of collidine hydrobromide which is collected on a filter (0.87 g.). The filtrate deposits a yellow, granuf lar, crude product upon pouring into ice water. The crude product is dissolved in chloroform and passed through a column containing activated carbon and a diatomaceous earth for partial purification. The glassy material remaining after evaporation of the chloroform is further purified by crystallization from methanol and then acetone-water and finally from ethyl acetate to give crystalling material, MP. 2145-216" 0., the ethyl acetate molecular complex of 17a,2l-diacetoxy-1,4-pregnadiene- 3,11,20-trione.

EXAMPLE 2 Preparation of 3 ,1 7 a-Dihy droxy-l -Methyl-17B-(1 -Ox0-2- Hydroxyethyl) -1,3,5 (10) -Eszratrien-1 I-One 2.2 grams (.0045 mole) of 3,17o-diacetoxy-1-methyl- 17B-(1-oxo-2-acetoxyethyl) 1,3,5(10) estratrien-ll-one obtained above is dissolved in 100 cc. of methanol and a solution of 0.976 gram (0181 mole) of sodium methylate in 60 cc. methanol is added under an atmosphere of nitrogen. The alkaline solution is aged ten minutes at 25 C., cooled to 5 C., acidified with 36% acetic acid, diluted with 200 cc. ice water and concentrated in vacuo to a volume of 200 cc. After cooling at 5 C. for five minutes, 720 mgms. of impure 3,17ot-dihydroxy-l-methyl- (1-=oxo-2-hydroxyethyl)-1,3,5(l0)-estratrienll-one is filtered off, M.P. 205-2l5 C. Further cooling for 1 hour of the filtrate gives a second crop (360 mgm.) of purer product melting at 245246 C. This fraction is recrystallized from acetone to constant melting point 25 6'- 257 C.

3,17ot-dihydroxy 1 methyl 17 8 (1-oxo-2-hydroxyethyl)-1,3,5(l0)-estratrien-l1-one is a crystalline solid freely soluble in half-normal potassium hydroxide solution in accordance with its formulation as a phenol. It gives a strongly positive tetrazolium test indicating the presence of the cortisone side chain. Upon paper strip chromatography, using methanol-forma'mide as the stationary phase and benzene or chloroform as the moving phase, the compound appears as a homogeneous single band.

Ultraviolet absorption in methanol:

max: E 277 mu 3020 283 (inflection) 2630 infra-red spectrum-in solid state shows hydroxyl absorption at 2.9-3.05/L, carbonyl at 5.85 and 5.95 1. and -C =C at 6.2 and 6.25 11 as in phenyl absorption. In ethanol solution, carbonyl absorption is observed at 581 (shoulder) and 5.86 -C=C at 6.19 and 6.26; the intensity suggests oxygen substitution (phenolic) and two carbonyl functions (C and C There is no indication of conjugated carbonyl or acetate groups as in the starting material, namely, 17a,21-dihydroxy-1,4-pregnudism-3,1 1,20-trione 17a,2l-diacetate.

EXAMPLE 3 Preparation 0 f 17ot-Hydroxy-3-Methoxy-1 -Methyl-1 7B- (1 Oxo-2-Hydroxyethyl)-1,3,5(10)-Estratrien-1 1 -One g. of 3,17 :x-dihydroxy 1 methyl-l7l3-(1-oxo-2-hydroxyethyl)-1,3,5 (10)-estratrien-11-one is stirred with 100 After evaporation of the ethereal solution, there is obtained 17ot-hydroxy 3 methoxy l methyl-l7fl-(1-oxo-2-hydroxyethyl) -1,3,5 10) -estratrien-l1-one. I

7 EXAMPLE 4 5 grams of 17a-hydroxy-3-methoxy-1-methyl-l7fi-( loxo 2 hydroxyethyl)-l,3,5 10)-estratrien-l1-one is reuntil the blue tetrazolium test for 20-ketol side chain is negative (approximately 24 hours). On evaporation of the chloroform and dilution with Water, the solid 17ahydroxy' 3 methoxy-l-methyl-l7/3-(I-sernicarbazono-Z- hydroxyethyl)-l,3,5(l)-estratrien-ll-one is filtered oil".

EXAMPLE Preparation 0 f I 1 8, J 7 a-Dihydr0xy-3-Zk ethoxy-1 -M ethyt 1 7-(] -Ox0-2-Hydroxyethy l) ,3,5 -Estratrierze EXAMPLE 6 Preparation 0 f I I fi-H y dr0xy-3-M ethoxy -M ethyl-1 7 20, 20,21-Bis-(Dioxymethylene) -1 ,3,5 (I 0) -Estratriene To 3.0 g. of 11 8,17a-dihydroxy-3-methoxy-l-methyl- 17,8-(1-0Xo 2 hydroxyethyl)-l,3,5(l0)-estratriene disof chloroform and 11B hydroxy 3 methoxy-l-methyl-17,20,20,21-bis-(dioxymethylene) -1,3,5(10) -estratriene.

EXAMPLE 7 Preparation of 11,8,17a-Dihydroxy-J-Met/1yl-17 6- (I-Ox 2-Hydr0xyethyl) -4-Estren-3-0ne The residue of 11 3-hydroxy-3-methoxy-1-methyl-17,20, 20,2l-bis-(dioxymethylene)-1,3,5(l0)-estratriene is dissolved in 100 ml. of ether and added ammonia in a dry ice bath. With stirring 5 g. of lithium the reduction mixture is digested added 60% formic acid and the mixture stirred at C. for 3 days to remove the enol ether and the bis-methylene ketal groupings. Chromatography of the product over activated magnesium silicate produces .pure 1 1 3, 1 7u-dihydr0xyl-methyl-l 7 8- 1-oxo-2-hydroxyethy1)-4-estren-3-one, activity.

which possesses anti-inflammatory EXAMPLE 8 Preparation 0 11,8,] 7a-Dihydr0xy-l -Methyl-1 7 3- (1 -0x0- Z-Acetoxyetlzyl) -4-Estren -3-One Treatment of the 11,8,l7a-dihydroxy-1-methyl-17,8-(1- oxo- -hydroxyethyl)-4-estren-3-one with pyridine and 1.1 molar equivalents of acetic anhydride at 60 for 1 hour yields substantially pure 11e,17a-dihydroxy-1methyl-17B- (1-oxo-2-acetoxyethyl)-4-estren-3-one upon the addition of water. The precipitated product is collected by filtration and dried at 40 C.

8 EXAMPLE 9 Preparation of 3,1 7a-Diacetoxy-l -MerIzyl-] 7 fi- J -Oxo-2- Acetoxyethyi ,3,5, J 0) ,6 -Eslratetraen-1 1 -One To a solution of mg. of 17a,2l-diacetoxy-1,4,6- pregnatrlene3,l1,20-trione (prepared as described hereinbelow) in 4 cc. of acetic anhydride is added 0.4 cc. of a 5% solution of anhydrous zinc chloride in glacial acetic acid. The solution is purged with nitrogen and stored at 25 C. for four days. It is then added to 80 cc. of ice Water and stirred until the acetic anhydride had hydrolyzed. The 3,17a-diacetoxy-l-methyl-l7,8(l-oxo-2- ac toxyethyl-1,3,5(l0)-6-estratetraen-l l-one is separated by extraction into ether. The ether extract is Washed with ice Water, cold 5% sodium ice Water, and dried over anhydrous solution is evaporated to dryness in vacuo resulting in 3,17a-diacetoxy l methyl-l7,B-(l-oxo2-acetoxyethyl)- 1,3,5 l0) ,6-estratetraen-1 l-one.

The l7a,21-diacetoxy-1,4,6-pregnatriene-3,11,20-trione used as a starting material in Example 9 is prepared starting with the known l7a,2l-dihydroxy-4-pregnene-3,1l,20- trione 2l-acetate in accordance with the following procedure:

200 mg. of p-toluene sulfonic acid is cc. benzene and heated until 40 cc. are distilled off. Isoadded and the mixture concentrated under reduced pressure at 35 40 C. e residue is triturated with 10 cc. dry benzene and reconcentrated. The residue contains 3,17a,21-triacetoxy-3,S-pregnadiene-l 1,20-dione.

l7oz,2l-dibromo 4 pregnene-3,l1,20-trione.

The 17a,2l-diacetoxy 6 bromo 4 pregnene-3,11,20 trione is dissolved in 5 cc. collidine and 12.5 cc. dimethyl fo The solution is heated at reflux temperature for two hours.

the residue contains 3,17a,21-triacetoxy 2,4 6 triene-1l,20-dione.

The crude 3,l7a,21-triacetoxy 2,4,6 pregnatriene- 11,20-dione from above is dissolved in cc. benzene and a solution of 6.05 grams (.034 mole) of N-bromosuccinrmide in 150 cc. dimethylformamide and 3.06 grams apnoea solid is filtered and washed free of acid with water. The

moist filter cake is dissolved in 150 cc. of chloroform, dried over sodium sulfate and concentrated in vacuo. The residue contains l7ot,21-diacetoxy 1,4,6 pregnatriene- 3,11,20-trione.

EXAMPLE 10 Preparation of 3,17ot-Dihydroxy-1 -Methyl-17 3-(1-0x0-2- H ydroxty-ethyl) -1 ,3 ,5 (1 ,-Estratetraen-l 1 -One The residue 3,l7a-diacetoxy-l-methyl-175%l-oxo-Z- acetoxyethyl)-1,3,5(10),6-estratetraen ll one obtained above is dissolved in cc. of methanol and a solution of 49 mgm. of sodium methylate in 5 cc. of methanol is added under an atmosphere of nitrogen. The alkaline solution is aged ten minutes at 25 C., cooled to 5 C., acidified with 36% acetic acid diluted with 20 cc. ice water and concentrated in vacuo to remove methanol. The steroid is extracted into chloroform. The extract is washed with ice water, dried over sodium sulfate and concentrated in vacuo. The residue 3,l7u.-dihydroxy lmethyl-UB-(l-oxo 2 hydroxyethyl)-1,3,5(l0),6-estratetraen-ll-one (80 mgm.) gives a positive tetrazolium test. It is purified by partition chromatography on a strip of thick filter paper using methanolformamide as the stationary phase and developed with chloroform. Two bands are obtained. The more polar main band is eluted with methanol and concentrated. The residue is distributed between chloroform-water to remove residual form- The dried chloroform layer upon evaporation gives a product which shows ultra-violet absorption in methanol solution characteristic of 3,l7ot-dihydroxy-lmethyl-17fi-(l-oxo 2 hydroxyethyl)l,3,5(l0),6-estratetraen-l l-one.

)\ max. E 222 mu 19,700 255 9,700

EXAMPLE 11 Preparation of 1 7 01-11 ydroxy-S-M ethoxy-l -M ethyl-1 7 g3- (1 Oxo-Z-Hydroxyethyl) -1 ,3,5 ,o-Estraretraen-l 1 -One g. of 3,l7a-dihydroxy-l-methyhl7{3-(l-oxo-Z-hydroxyethyl)-l,3,5(l0),6-estratetraen ll one is stirred with 100 ml. of ethereal diazomethane solution for 24 hours. After evaporation of the ethereal solution, there is obtained 17a-hydroxy 3 methoxy-l-methyl-l7B-(loxo-Z-hydroxyethyl) -1 ,3 ,5 (l0) ,o-estratetraenl i -one.

EXAMPLE 12 Preparation 0 1 7e-Hydr0xy-3-Merhoxy-1 -Methyl-1 7 p- (1 Semicarbazono 2 Hydroxyethyl) -1 ,3 ,5 (1 0) ,6-Estratetraen-11-One 5 grams of l7a-hydroxy 3 methoxy-l-methyl-flp- (l-oxo-Z-hydroxyethyl) l,3,5(l0),6 estratetraen-llone is refluxed with a solution of 5 g. of semicarbazide free base in 20 ml. of dimethylformamide and 20 ml. of chloroform until the blue tetrazolium test for ZO-ketol side chain is negative (approximately 24 hours). On evaporation of the chloroform and dilution with water, the solid l7ot-hydroxy 3 methoxy-1-methyl-17B-(1- semicarbazono-Z-hydroxyethyl) 1,3,5(10),6 estratetraen-ll-one is filtered off.

EXAMPLE. 1?:

Preparation of 11 ,6,17a-Dihydr0xy-3-Meth0xy-1-Methyl- 17fi-(1-Oxo-2-Hydroxyethyl) -1,3,5 (10) ,o-Estrateraene The 17 a-hydroxy-S-methoxy-l-rnethyl-l7 B- l-sernicarbazono Z-hydroxyethyl) -l ,3 ,5 l0) ,6-estratetraen-l l-one obtained above is dissolved in ml. of tetrahydroiuran and 20 ml. oi water. 10 g. of sodium borohydride is added to the reaction mixture and it is agitated for 2 hours at 20 C. After evaporation of the solvent, dilution of the residue with hydrochloric acid and water, and filtration, the residual product is crystallized from ethyl acetate to yield pure llo,l7e-dihydroxy-3-methoxy-1-methyl-l7fi- (l-oxo-Z-hydroxyethyl) -l ,3 ,5 l0) ,6-estratetraen.

EXAMPLE 14 Preparation of 11fi-Hydr0xy-3-1l Iethoxy-1-Methyl-17,20, 20,21 -Bis-(Dioxymethylene)-1 ,3 ,5 (1 0),6-Estratetraene To 3.0 g. of l1(3,l7a-dihydroxyd-methoxy-l-methyll7[3-( l-oxo-Z-hydroxyethyl) -1,3 ,5 (l0) ,-estratetraene dissolved in 10 ml. of chloroform and 10 ml. of formalin is added 5 cc. of concentrated hydrochloric acid to form 11- hydroxy 3 methoxy l-rnethyl-l7,20,20,2l-bis-(dioxymethylene)-l,3,4(l0),6-estratetraene. After 48 hours at room temperature, the acid is neutralized with 10% sodium hydroxide solution. The chloroform layer is separated and concentrated to dryness to yield lie-hydroxy 3-methoxy-l-methyl-l7.2020,2l-bis(dioxyrnethylone) -1 ,3 ,5 (l0) ,6-estratetraen.

EXAMPLE 15 Preparation of 115,17u-Dihydr0xy-1-Methyl-17B-(1-0x0- Z-Hydroxy ethyl) -4 ,o-Estradi 811-3 -One The residue of llfi-hydroxy-3-methoxy-l-methyl-l7,20, 20,21 bis-(dioxymethylene) -l,3,5 l0) ,-estratetraen, is dissolved in 100 ml. of ether and added to 100 ml. of liquid ammonia in a dry ice bath. With stirring, 5 g. of lithium is added and the mixture stirred for 24 hours. Ethyl acetate is then added to discharge the excess lithium and the ammonia removed by evaporation. The residue of reduced compound was digested with water and filtered. To the reduced compound is added 60% formic acid and the mixture stirred at 20 C. for 3 days to remove the enol ether and the bismethylene ketal groupings. Chromatography of the product over activated magnesium silicate produces pure ll{3,17ct-dihydroxy-l-methyl-l7,8-(1-oxo-2- hydroxyethyl)4,6-estradiene3-one, which posses anti-infiamrnatory activity.

EXAMPLE 16 Preparation of 116,17ot-Dihydr0xy-1-Methyl-17B-(1-Oxc 2 -A cetoxyethy l -4 ,6 --Estradi ens-3 -One 115,17e dihydroxy l-rnethy -17 ,o-(l-oxo-2-hydroxyethyl) -4,6-estradiene-3-one is heated with pyridine and 1.1 molar equivalents of acetic anhydride at 60 C. for 2 hours. On addition of water ll6,l7ot-dihydroxy-l-methyll7-(l-oxo-2-acetoxyethyl) 4,6 estradiene-3-one is obtained and collected by filtration.

It should be understood that various changes may be made in the present process as herein described without afiecting the results attained. Thus, various modifications of conditions as to time, temperature, etc. and various changes in procedure differing from those herein given as illustrative of the preferred embodiments of this invention may be made without departing from the scope of our invention is to be determined in accordance with the prior art and the appended claims.

What is claimed is:

l. 3,17a diaceto-xy 1 methyl-17,84l-oxo-Z-acetoxyethyl) l ,3 ,5 (10)-estratrien-l l-one.

2. 3,1700 dihydroxy 1-methyl-17B-(l-oxoQ-hydroxyethyl) l ,3,5 l0) -estratrien-l l-one.

3. 17oz hydroxy 3 methyl-l-methyl-UB-(l-semicarbazono-2-hydroxyethyl) -1,3 ,5 10) -estratrien-l l-one.

6. 3,170: dihydroxy l-methy1-17,8-(1oxo-2-hydroxy- 5 ethyl) -1,3,5 10),6-estratetraen-1 I-one.

7. 170: hydroxy-3-meth0xy-1-methy1-17,8-(1-0Xo-2-hydr0Xyethy1)-1,3,5(10),6-estratetraen-1l-one.

17 a hydroxy-S-methoxy-i-methyI-l7,8- l-semicarbazono-Z-hydroxyethyl) -1,3,5 10) ,6-estratetraen-1 l-one.

9. 115,17oa-dihydroXy-3 -meth0Xy-1-methy1-17B-( 1OXO- Z-hydroxyethyl) -1,3,5 l0) ,6-est-ratetraene.

10. 1 1,8 hydr0Xy-3 -meth0xy-1-methy1-17,20,20,2l-bis- (dioxymethylene) -1,3,5(10) ,6-estratetraene.

References Cited in the file of this patent UNITED STATES PATENTS 2,837,464 Nobiie June 3, 1958 2,840,581 Hogg et a1 June 24, 1958' 2,863,862 Djerassi et a1 Dec. 9, 1958 2,866,799 Beyler et a1 Dec. 30, 1958 2,977,284 Agnello et a1 Mar. 28, 1961 OTHER REFERENCES Dje-rassi: J.A.C.S., vol. 72 (1950), p. 4542 relied on. Copy in Scientific Library.

Hershberg: J.A.C.S., v01 79 (1957) p. 502 relied on. Copy in Scientific Library.

Agnello et -a1.: 3.A.C.S., v01 79 (1957), p. 1258 relied on. Copy in Scientific Library.

Wendler et a1.: 5. Am. Chem. Soc., vol. 73 (August 15 1951), pages 38183820. Copy in Patent Office Scientific Library.

Magerlein et aL: J. Am. Chem. Soc., vol. 79 (March 20, 1597), pages 1508 and 1509. Copy in Patent Ofiice Scientific Library. 

4. 11B - HYDROXY-3-METHOXY-1-METHYL-17,20,20,21-BIS(DIOXYMETHYLENE)-1,3,5(10) -ESTRATRIENE.
 10. 11B - HYDROXY-3-METHOXY-1-17,20,20,21-BIS(DIOXYMETHYLENE)-1,3,5(10).6 -ESTRATETRAENE. 